Axonal disconnection in the central nervous system (CNS) can result in persistent deficits in many neurological disorders, such as spinal cord injury (SCI), because axons in the mammalian CNS do not regenerate. Failure of axon regeneration in CNS is believed to be due to both a non-permissive environment, including myelin-associated growth inhibitors (3, 4), scar-sourced chondroitin sulfate proteoglycans (5, 6), repulsive axon guidance cues (7, 8) and lack of neurotraphic factors (9-11), and the reduced intrinsic growth capacity of mature neurons (12). Several cell autonomous molecules, including cAMP, RhoA, Kruppel-like factors, mammalian target of rapamycin (mTOR) and phosphatase and tensin homolg (PTEN), have been reported to play roles in determining neuronal growth ability (13-16). PTEN appears to be particularly important for controlling the regenerative capacity of injured axons (2).
Conditional deletion of PTEN, a negative regulator of mTOR, has been shown to enhance axon growth after SCI or optic nerve injury and protect retinal ganglion cells (RGCs) from death following axotomy (14, 16, 17). The axon growth-promoting action of PTEN deletion is reduced by the mTOR inhibitor rapamycin. Deletion of tuberous sclerosis complex 1 (TSCI), a negative regulator of mTOR, also activated mTOR and enhanced axon regeneration by principally mimicking the effect of PTEN deficiency. PTEN deletion or inhibition has been reported to stimulate axon growth of several neuronal populations, including RGCs, dorsal root ganglion (DRG) sensory neurons, corticospinal tract (CST) and other motor neurons (2, 14, 16, 18, 19). In addition, PTEN blockade with general phosphatase inhibitor bisperoxovanadium (bpV) protected spinal cord tissues after SCI (20, 21). Application of bpV may block PTEN function (18) but bpV compounds also target other enzymes and may cause clinical side effects. Therefore, there remains a need for efficient and selective reduction of PTEN activity.